The present invention relates to a method for the treatment and prevention of sepsis and septic shock by using metal:thiol complexes. The present invention also relates to the use of metal:thiol complexes to modulate the immune system.
Sepsis results from an infection and is manifested clinically by fever or hypothermia, increased heart and respiratory rates, abnormal white blood cell count, and evidence of systemic hypoperfusion. It is accompanied by a number of cellular and biochemical changes in the immune system. Septic shock is a condition that usually develops as a complication of overwhelming sepsis. Worldwide statistics on sepsis or septic shock are not known. However, sepsis is a frequent cause of death in the USA and accounts for a substantial health-related costs annually. A study of sepsis and septic shock between 1979-1987 has demonstrated a progressive increase in their incidence despite the development of more potent antibiotics, supportive therapy and critical care medicine. Although precise recent data are not available, it was estimated that 100,000 to 400,000 patients develop sepsis annually in the United States; half of these patients develop septic shock with a mortality rate ranging between 20% and 80% depending upon the definition of the syndrome. More than 70-80% of all cases of septic shock were caused by gram-negative organisms. However, recent trends show an increase in the incidence of gram positive bacteria (30-40%), virus- and fungi-related sepsis which previously were considered to be minority causes of sepsis.
Many therapies that have been used to treat or prevent septic shock have proven insufficient. These approaches include (1) eliminating the causal agents (that cause the release of toxins and cell wall product), or (2) using antibodies against the inflammatory mediators. It has been theorized that morbidity and mortality from sepsis and septic shock arise from emergence of the anti-inflammatory cytokines or mediators that cause immunosuppression. It has been suggested that boosting the immune system may prove beneficial. However, any attempt to put this into clinical practice risks inflammatory effects of the agents used, in a compromised system.
Bismuth has been known for many years as an antibacterial agent and has been used against Helicobacter pylori. The subcitrate forms of Bismuth are used as anti-diarrheal and anti-septic agents and some other purposes. The potency or efficacy of these compounds are low, especially in the presence of iron. In addition, insolubility of Bismuth in water decreased its effectiveness substantially thus restricting its use.
It is an object of the present invention to provide methods to treat and prevent sepsis and septic shock.
It is another object of the invention to provide methods to modulate the immune system.
In one embodiment, the invention provides a method of treating or preventing sepsis or septic shock by administering to a subject in need of such treatment or prevention, a formulation comprising an immunomodulating agent selected from the group consisting of:
(A) a mixture comprising (i) a complexing agent having at least one thiol group, and (ii) a group V metal or compound thereof said Group V metal being selected from the group consisting of bismuth, antimony and arsenic;
(B) a complex whose molecular structure includes (i) a complexing agent having at least one thiol group, (ii) a Group V metal or compound thereof said Group V metal being selected from the group consisting of bismuth, arsenic and antimony; and (iii) a coordinate bond linking at least one sulfur atom of the thiol-containing complexing agent of subparagraph (B)(i) to the metal of subparagraph (B)(ii); and
(C) a combination comprising the complex of paragraph (B) and at least one specie selected from the group consisting of (i) a thiol-containing complexing agent and (ii) a Group V metal or compound thereof, said Group V metal, being selected from the group consisting of bismuth antimony and arsenic.
The term xe2x80x9cthiolxe2x80x9d is used herein to refer to a compound that contains one or more sulfur atoms capable of existing in the form of sulfhydryl groups under appropriate pH conditions, regardless of whether such sulfur atoms are deprotonated or fully or partially protonated under conditions in which the thiol is used, and regardless of the pH under which it is used. xe2x80x9cThiol groupxe2x80x9d means a sulfur or an xe2x80x94SH group of a xe2x80x9cthiolxe2x80x9d.
The terms xe2x80x9cmixturexe2x80x9d and xe2x80x9ccombinationxe2x80x9d encompass the use of two or more components in sufficiently close proximity to each other that they may interact with each other under conditions of end use for the immunomodulating agent of the invention, or for products which include said agent in accordance with the invention. Patients in need of treatment for a particular disease are those displaying symptoms or responding to diagnostic tests indicating presence of the disease in question. Patients in need of prophylactic intervention are those who through exposure or otherwise are at higher risk of contracting the disease in question than is the general population.
Immunomodulating agents described herein may be used to modulate the immune system and more specifically to prevent or alleviate an immunosuppression state which can occur for example in sepsis and septic shock.
In another embodiment, the invention provides a method of modulating the immune response in a subject comprising administering to said subject a formulation comprising an immunomodulating agent selected from the group consisting of:
(A) a mixture comprising (i) a complexing agent having at least one thiol group, and (ii) a group V metal or compound thereof said Group V metal being selected from the group consisting of bismuth, antimony and arsenic;
(B) a complex whose molecular structure includes (i) a complexing agent having at least one thiol group, (ii) a Group V metal or compound thereof said Group V metal being selected from the group consisting of bismuth, arsenic and antimony; and (iii) a coordinate bond linking at least one sulfur atom of the thiol-containing complexing agent of subparagraph (B)(i) to the metal of subparagraph (B) (ii); and
(C) a combination comprising the complex of paragraph (B) and at least one specie selected from the group consisting of (i) a thiol-containing complexing agent and (ii) a Group V metal or compound thereof, said Group V metal, being selected from the group consisting of bismuth, antimony and arsenic.
Other features and advantages of the present invention will become apparent from the following description of the invention which refers to the accompanying drawings.